EP1545553A1 - Use of alkyl phosphocholines in combination with antitumor medicaments - Google Patents

Use of alkyl phosphocholines in combination with antitumor medicaments

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Publication number
EP1545553A1
EP1545553A1 EP03766336A EP03766336A EP1545553A1 EP 1545553 A1 EP1545553 A1 EP 1545553A1 EP 03766336 A EP03766336 A EP 03766336A EP 03766336 A EP03766336 A EP 03766336A EP 1545553 A1 EP1545553 A1 EP 1545553A1
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EP
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Prior art keywords
treatment
alkylphosphocholines
tumor
general formula
formula
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EP03766336A
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German (de)
French (fr)
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EP1545553B1 (en
Inventor
Jürgen Engel
Eckhard Günther
Herbert Sindermann
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Aeterna Zentaris GmbH
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Zentaris AG
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Priority to SI200332027T priority Critical patent/SI1545553T1/en
Priority to EP10010451A priority patent/EP2301551A1/en
Publication of EP1545553A1 publication Critical patent/EP1545553A1/en
Application granted granted Critical
Publication of EP1545553B1 publication Critical patent/EP1545553B1/en
Priority to CY20111100944T priority patent/CY1111902T1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Alkylphosphocholines are a new class of organic compounds that show diverse antineoplastic activities (M. Lohmeyer and R. Bittman; Antitumor ether lipids and alkylphosphocholines, DOF, 19 (11), 1021-1037 (1994)).
  • the effect of the alkylphosphocholines can be based on various molecular and biochemical mechanisms, some of which take place at the level of the plasma membrane of the cell.
  • the influence of alkylphosphocholines on inositol metabolism, the interaction with phospholipases or the inhibition of protein kinase C and thus a general influence on the signal transduction of the cell by this class of substances is well known (K. Maly, F. fürall, C. Schubert, E Kindler, J.
  • the alkylphosphocholine perifosine shows growth-inhibitory properties against various melanoma, CNS, lung, colon, prostate and breast cancer cell lines with an IC 5 o in the range from 0.2-20 ⁇ M (P. Hilgard, T. Kienner, J. Stekar, G. Nössner, B. Kutscher and J. Engel; D-21266, a New Heterocyclic Alkylphospholipid with Antitumor Activity, Eur. J. Cancer, 33 (3), 442-446 (1997)).
  • perifosine blocks tumor cells in the GiS and G 2 -M phase of the cell cycle (V. Patel, T. Lahusen, T. Sy, EA Sausville, JS Gutkind and AM Senderowicz; Perifosine, a Novel Alkylphospholipid, Induces p21 Waf1 Expression in Squamous Carcinoma Cells through a p53-independent Pathway, Leading to Loss in Cyclin-dependent Kinase Activity and Cell Cycle Arrest, Cancer Research 62, 1401-1409 (2002)).
  • linear alkylphosphocholines of the general formula I and II are suitable for being used in a combination according to the invention with other medicaments for the treatment of benign and malignant tumor diseases in humans and mammals.
  • the compounds of general formulas I and II can be used in a combination according to the invention with antitumor substances.
  • Antitumor substances can be alkylating agents, antimetabolites, plant alkaloids, platinum compounds, tumor antibiotics and agonists or antagonists of natural hormones.
  • the antitumor substances can be selected from, but not limited to: cisplatin, carboplatin, oxaliplatin, bleomycin, doxorubicin, methotrexate, paclitaxel, docetaxel, vincristine, vinblastine, etoposide, teniposide, ifosfamide, cyclophosphamide, 5-fluorourtararabinacil, fludarabinacil, fludarabinol ,
  • alkylphosphocholines of the general formulas I and II can be used in a claimed combination with inhibitors of signal transduction, in the form of high and low molecular weight inhibitors of receptor and / or cytosolic kinases.
  • inhibitors of signal transduction in the form of high and low molecular weight inhibitors of receptor and / or cytosolic kinases.
  • These inhibitors can be selected, but not limited to, monoclonal antibodies and heterocyclic compounds.
  • alkylphosphocholines of the general formula I and II on which the invention is based can be used in the form of finished medicinal products.
  • the compounds on which the invention is based are described by the general formulas I and II:
  • n, m, p, z represent an integer between 0 and 4;
  • RH a straight-chain or branched (CrC 2 o) -alkyl radical, which can be saturated or unsaturated with one to three double and / or triple bonds and which is unsubstituted or optionally on the same or different C atoms with one or two or more halogen, nitro, cyano, hydroxy, (-C-C 6 ) alkoxy, amino, mono- (CC 4 ) alkylamino or di- (CrC) alkylamino radicals can be substituted.
  • Ri, R 2 , R 3 independently of one another H, a straight-chain or branched (Cr C 6 ) -alkyl radical, preferably methyl and ethyl, a (C 3 -C 7 ) -cycloalky radical and which is unsubstituted or optionally on the same or different carbon atoms with one, two or more halogen, nitro, cyano, hydroxy, (CrC 6 ) alkoxy, amino, mono- (CrC 4 ) alkylamino or di- (-C 4 ) alkylamino residues can be means.
  • a straight-chain or branched (Cr C 6 ) -alkyl radical preferably methyl and ethyl
  • a (C 3 -C 7 ) -cycloalky radical and which is unsubstituted or optionally on the same or different carbon atoms with one, two or more halogen, nitro, cyano, hydroxy, (CrC 6
  • a method for combating tumors in humans and in mammals which is characterized in that at least one compound according to the invention according to general formulas I and II is used in humans or in a mammal for the purposes of Tumor treatment effective amount is administered before or during treatment with approved anti-tumor substances.
  • the therapeutically effective dose to be administered for the treatment of the respective compound of the general formula I and II on which the invention is based depends, inter alia. according to the type and stage of the tumor, the age and sex of the patient, the type of administration and the duration of treatment.
  • the compounds on which the invention is based can be administered in a pharmaceutical as liquid, semi-solid and solid pharmaceutical forms. This takes place in the most suitable manner in the form of aerosols, powders, powders and scattering powders, tablets, dragees, emulsions, foams, solutions, suspensions, gels, ointments, pastes, pills, lozenges, capsules or suppositories.
  • the induction of breast cancer was carried out by a single oral administration of DMBA.
  • the animals received perifosin from day 0 to day 14 and were observed until day 42.
  • the weight of the tumor mass was determined by palpation and comparison with plastic models. The initial weight is set to 100%.
  • the induction of breast cancer was carried out by a single oral administration of DMBA.
  • the animals received perifosin from day 0 to day 14 and were observed until day 42.
  • the weight of the tumor mass was determined by palpation and comparison with plastic models. The initial weight is set to 100%.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to the use of alkyl phosphocholines in combination with antitumor medicaments for treating benign and malignant tumor diseases in humans and mammals. The alkyl phosphocholines can be used in an inventive combination with one or a combination of several approved cytostatics. Preferred alkyl phosphocholines are represented in formula II.

Description

ANWENDUNG VON A KY PHOSPHOCHO INΞN IN KOMBINATION MIT ANTITUMORMEDIKAMENTEN APPLICATION OF A KY PHOSPHOCHO INΞN IN COMBINATION WITH ANTITUM ORMEDICAMENTS
Alkylphosphocholine sind eine neue Klasse organischer Verbindungen, die vielfältige antineoplastische Aktivitäten zeigen (M. Lohmeyer und R. Bittman; Antitumor ether lipids and alkylphosphocholines, DOF, 19 (11 ), 1021-1037 (1994)). Die Wirkung der Alkylphosphocholine kann dabei auf verschiedenen molekularen und biochemischen Mechanismen beruhen, die zum Teil auf Ebene der Plasmamembran der Zelle stattfinden. Gut bekannt ist der Einfluß der Alkylphosphocholine auf den Inositol- Metabolismus, die Interaktion mit Phospholipasen oder die Hemmung der Protein Kinase C und damit eine generelle Beeinflussung der Signaltransduktion der Zelle durch diese Stoffklasse (K. Maly, F. Überall, C. Schubert, E. Kindler, J. Stekar, H. Brachwitz und H. H. Grunicke, Interference of new alkylphospholipid analogues with mitogenic Signal transduction, Anti-Cancer Drug Design, 10, 411-425 (1995)). So zeigt das Alkylphosphocholine Perifosine wachstums-inhibitorische Eigenschaften gegenüber verschiedenen Melanom-, CNS-, Lunge-, Colon-, Prostata- und Brustkrebszelllinien mit einer IC5o im Bereich von 0.2 - 20 μM (P. Hilgard, T. Kienner, J. Stekar, G. Nössner, B. Kutscher und J. Engel; D-21266, a New Heterocyclic Alkylphospholipid with Antitumor Activity, Eur. J. Cancer, 33 (3), 442-446 (1997)). Des weiteren ist bekannt, daß Perifosine Tumorzellen in der G-i-S und G2-M Phase des Zellzyklus blockiert (V. Patel, T. Lahusen, T. Sy, E. A. Sausville, J. S. Gutkind und A. M. Senderowicz; Perifosine, a Novel Alkylphospholipid, Induces p21Waf1 Expression in Squamous Carcinoma Cells through a p53-independent Pathway, Leading to Loss in Cyclin-dependent Kinase Activity and Cell Cycle Arrest, Cancer Research 62, 1401-1409 (2002)).Alkylphosphocholines are a new class of organic compounds that show diverse antineoplastic activities (M. Lohmeyer and R. Bittman; Antitumor ether lipids and alkylphosphocholines, DOF, 19 (11), 1021-1037 (1994)). The effect of the alkylphosphocholines can be based on various molecular and biochemical mechanisms, some of which take place at the level of the plasma membrane of the cell. The influence of alkylphosphocholines on inositol metabolism, the interaction with phospholipases or the inhibition of protein kinase C and thus a general influence on the signal transduction of the cell by this class of substances is well known (K. Maly, F. Überall, C. Schubert, E Kindler, J. Stekar, H. Brachwitz and HH Grunicke, Interference of new alkylphospholipid analogues with mitogenic Signal transduction, Anti-Cancer Drug Design, 10, 411-425 (1995)). The alkylphosphocholine perifosine shows growth-inhibitory properties against various melanoma, CNS, lung, colon, prostate and breast cancer cell lines with an IC 5 o in the range from 0.2-20 μM (P. Hilgard, T. Kienner, J. Stekar, G. Nössner, B. Kutscher and J. Engel; D-21266, a New Heterocyclic Alkylphospholipid with Antitumor Activity, Eur. J. Cancer, 33 (3), 442-446 (1997)). It is also known that perifosine blocks tumor cells in the GiS and G 2 -M phase of the cell cycle (V. Patel, T. Lahusen, T. Sy, EA Sausville, JS Gutkind and AM Senderowicz; Perifosine, a Novel Alkylphospholipid, Induces p21 Waf1 Expression in Squamous Carcinoma Cells through a p53-independent Pathway, Leading to Loss in Cyclin-dependent Kinase Activity and Cell Cycle Arrest, Cancer Research 62, 1401-1409 (2002)).
Es ist bekannt, daß der Einsatz von Alkylphosphocholinen vor oder zusammen mit der Strahlentherapie zu synergistischen Effekten bei der Behandlung von Tumoren führt (G.A. Ruitter, M. Verheijl, S. F. Zerp und W. J. van Blitterswijk; Alkyl- Lysophospholipids as Anticancer Agents and Enhancers of Radiation-Induced Apoptosis, Int. J. Radiation Oncology Biol. Phys., 49 (2), 415-420, 2001 ). Es wurde ferner berichtet, daß verschiedene Glycero-3-phospholipide, z.B. ET-18-OCH3 in Kombination mit verschiedenen DNA-interagierenden Substanzen oder Tubulin- Bindern die Antitumor Aktivität in-vitro an verschiedenen Tumorzelllinien erhöhen (A. Noseda, M. E. Berens, J. G. White und E. J. Modest; In vitro antiproliferative activity of combinations of ether lipid analogs and DNA- Interactive agents against human tumor cells, Cancer Res., 48 (7), 1788-1791 (1988); P. Principe, H. Coulomb, C. Broquet und P. Braquet; Evaluation of combinations of antineoplastic ether phospholipids and chemotherapeutic drugs, Ant-Cancer Drugs, 3 (6), 577-587 (1992); P. Principe, H. Coulomb, J.-M. Mencia-Huerta, C. Broquet und P. Braquet; Synergistic cytotoxic effect of aza-alkylphospholipids in association with chemotherapeutic drugs, J. Lipid Mediators Cell Signalling, 10 (1-2), 171-173 (1994)).It is known that the use of alkylphosphocholines before or together with radiation therapy leads to synergistic effects in the treatment of tumors (GA Ruitter, M. Verheijl, SF Zerp and WJ van Blitterswijk; Alkyl- Lysophospholipids as Anticancer Agents and Enhancers of Radiation- Induced Apoptosis, Int. J. Radiation Oncology Biol. Phys., 49 (2), 415-420, 2001). It has also been reported that various glycero-3-phospholipids, for example ET-18-OCH 3 in Combination with various DNA-interacting substances or tubulin binders increases the antitumor activity in vitro on different tumor cell lines (A. Noseda, ME Berens, JG White and EJ Modest; In vitro antiproliferative activity of combinations of ether lipid analogs and DNA-Interactive agents against human tumor cells, Cancer Res., 48 (7), 1788-1791 (1988); P. Principe, H. Coulomb, C. Broquet and P. Braquet; Evaluation of combinations of antineoplastic ether phospholipids and chemotherapeutic drugs, Ant- Cancer Drugs, 3 (6), 577-587 (1992); P. Principe, H. Coulomb, J.-M. Mencia-Huerta, C. Broquet and P. Braquet; Synergistic cytotoxic effect of aza-alkylphospholipids in association with chemotherapeutic drugs, J. Lipid Mediators Cell Signaling, 10 (1-2), 171-173 (1994)).
Es konnte jetzt überraschend gezeigt werden, daß lineare Alkylphosphocholine der allgemeinen Formel I und II geeignet sind, in einer erfindungsgemäßen Kombination mit anderen Arzneimitteln zur Behandlung von gut- und bösartigen Tumorerkrankungen am Menschen und Säugetier eingesetzt zu werden. Dabei können die Verbindungen der allgemeinen Formel I und II in einer erfindungsgemäßen Kombination mit Antitumor-Substanzen eingesetzt werden. Antitumor-Substanzen können Alkylanzien, Antimetabolite, Pflanzenalkaloide, Platinverbindungen, Tumorantibiotika und Agonisten bzw. Antagonisten natürlicher Hormone sein. Die Antitumor-Substanzen können ausgewählt aber nicht darauf beschränkt sein aus: Cisplatin, Carboplatin, Oxaliplatin, Bleomycin, Doxorubicin, Methotrexat, Paclitaxel, Docetaxel, Vincristine, Vinblastine, Etoposid, Teniposid, Ifosfamid, Cyclophosphamid, 5-Fluorouracil, Fludarabin, Gemcitabin und Cytarabin.It has now surprisingly been possible to show that linear alkylphosphocholines of the general formula I and II are suitable for being used in a combination according to the invention with other medicaments for the treatment of benign and malignant tumor diseases in humans and mammals. The compounds of general formulas I and II can be used in a combination according to the invention with antitumor substances. Antitumor substances can be alkylating agents, antimetabolites, plant alkaloids, platinum compounds, tumor antibiotics and agonists or antagonists of natural hormones. The antitumor substances can be selected from, but not limited to: cisplatin, carboplatin, oxaliplatin, bleomycin, doxorubicin, methotrexate, paclitaxel, docetaxel, vincristine, vinblastine, etoposide, teniposide, ifosfamide, cyclophosphamide, 5-fluorourtararabinacil, fludarabinacil, fludarabinol ,
Des weiteren können die Alkylphosphocholine der allgemeinen Formel I und II in einer beanspruchten Kombination mit Hemmstoffen der Signaltransduktion, in Form von hoch- und niedermolekularen Inhibitoren von Rezeptor- und/oder cytosolischen Kinasen eingesetzt werden. Diese Hemmstoffe können ausgewählt aber nicht darauf beschränkt sein auf Monoclonale Antikörper und heterocyclische Verbindungen.Furthermore, the alkylphosphocholines of the general formulas I and II can be used in a claimed combination with inhibitors of signal transduction, in the form of high and low molecular weight inhibitors of receptor and / or cytosolic kinases. These inhibitors can be selected, but not limited to, monoclonal antibodies and heterocyclic compounds.
Die der Erfindung zugrunde liegenden Alkylphosphocholine der allgemeinen Formel I und II können in Form von Fertigarzneimitteln zur Anwendung gelangen. Die der Erfindung zugrunde liegenden Verbindungen werden durch die allgemeinen Formeln I und II beschrieben:The alkylphosphocholines of the general formula I and II on which the invention is based can be used in the form of finished medicinal products. The compounds on which the invention is based are described by the general formulas I and II:
Formel formula
°~ W" ra Formel II° ~ W " ra formula II
wobei unabhängig voneinander:independently of each other:
n, m, p, z eine ganze Zahl zwischen 0 und 4 bedeuten;n, m, p, z represent an integer between 0 and 4;
X O, S, NH;X O, S, NH;
R H, einen geradkettigen oder verzweigten (CrC2o)-Alkyl-Rest, welcher gesättigt oder mit ein bis drei Doppel- und/oder Dreifachbindungen ungesättigt sein kann und welcher unsubstituiert oder wahlweise an dem gleichen oder an verschiedenen C-Atomen mit ein, zwei oder mehreren Halogen, Nitro, Cyano, Hydroxy, (Cι-C6)-Alkoxy, Amino, Mono-(C C4) Alkylamino oder Di- (CrC )-Alkylamino Resten substituiert sein kann, bedeutet.RH, a straight-chain or branched (CrC 2 o) -alkyl radical, which can be saturated or unsaturated with one to three double and / or triple bonds and which is unsubstituted or optionally on the same or different C atoms with one or two or more halogen, nitro, cyano, hydroxy, (-C-C 6 ) alkoxy, amino, mono- (CC 4 ) alkylamino or di- (CrC) alkylamino radicals can be substituted.
Ri, R2, R3 unabhängig von einander H, einen geradkettigen oder verzweigten (Cr C6)-Alkyl-Rest, vorzugsweise Methyl und Ethyl, einen (C3-C7)-Cycloalky- Rest und welcher unsubstituiert oder wahlweise an dem gleichen oder an verschiedenen C-Atomen mit ein, zwei oder mehreren Halogen, Nitro, Cyano, Hydroxy, (CrC6)-Alkoxy, Amino, Mono-(CrC4) Alkylamino oder Di- (Cι-C4)-Alkylamino Resten substituiert sein kann, bedeutet. Gemäß einem weiteren Aspekt der Erfindung wird ein Verfahren zur Bekämpfung von Tumoren beim Menschen und in Säugetieren bereit gestellt, welches dadurch gekennzeichnet ist, daß mindestens eine der Erfindung zugrunde liegenden Verbindungen gemäß der allgemeinen Formel I und II dem Menschen oder einem Säugetier in einer für die Tumorbehandlung wirksamen Menge vor oder während einer Behandlung mit zugelassenen Antitumor-Substanzen verabreicht wird.Ri, R 2 , R 3 independently of one another H, a straight-chain or branched (Cr C 6 ) -alkyl radical, preferably methyl and ethyl, a (C 3 -C 7 ) -cycloalky radical and which is unsubstituted or optionally on the same or different carbon atoms with one, two or more halogen, nitro, cyano, hydroxy, (CrC 6 ) alkoxy, amino, mono- (CrC 4 ) alkylamino or di- (-C 4 ) alkylamino residues can be means. According to a further aspect of the invention, there is provided a method for combating tumors in humans and in mammals, which is characterized in that at least one compound according to the invention according to general formulas I and II is used in humans or in a mammal for the purposes of Tumor treatment effective amount is administered before or during treatment with approved anti-tumor substances.
Die für die Behandlung zu verabreichende therapeutisch effektive Dosis der jeweiligen der Erfindung zugrunde liegenden Verbindung der allgemeinen Formel I und II richtet sich u.a. nach der Art und dem Stadium der Tumorerkrankung, dem Alter und Geschlecht des Patienten, der Art der Verabreichung und der Dauer der Behandlung.The therapeutically effective dose to be administered for the treatment of the respective compound of the general formula I and II on which the invention is based depends, inter alia. according to the type and stage of the tumor, the age and sex of the patient, the type of administration and the duration of treatment.
Die der Erfindung zugrunde liegenden Verbindungen können in einem Arzneimittel als flüssige, halbfeste und feste Arzneiformen verabreicht werden. Dies erfolgt in der jeweils geeigneten Weise in Form von Aerosolen, Pulver, Puder und Streupuder, Tabletten, Dragees, Emulsionen, Schäume, Lösungen, Suspensionen, Gele, Salben, Pasten, Pillen, Pastillen, Kapseln oder Suppositorien.The compounds on which the invention is based can be administered in a pharmaceutical as liquid, semi-solid and solid pharmaceutical forms. This takes place in the most suitable manner in the form of aerosols, powders, powders and scattering powders, tablets, dragees, emulsions, foams, solutions, suspensions, gels, ointments, pastes, pills, lozenges, capsules or suppositories.
Ausführungsbeispiele:EXAMPLES
1. Gabe von Perifosine (D-21 266) in Kombination mit Cisplatin1. Administration of Perifosine (D-21 266) in combination with cisplatin
In-vivo Versuch: DMBA induziertes Mamma-Karzinom Modell an der RatteIn-vivo experiment: DMBA-induced breast carcinoma model in the rat
Versuchstier: Sprague-Dawley Ratte, weiblichExperimental animal: Sprague-Dawley rat, female
Durchführung: Die Induktion des Mamma-Karzinoms erfolgte durch einmalige orale Gabe von DMBA. Die Tiere erhielten von Tag 0 bis Tag 14 Perifosin und wurden bis Tag 42 beobachtet. Das Gewicht der Tumormasse wurde mittels Palpation und Vergleich mit Plastikmodellen ermittelt. Das Ausgangsgewicht wird gleich 100% gesetzt. Gabe: Perifosin 14 x 6.81 mg/kg p.o.Implementation: The induction of breast cancer was carried out by a single oral administration of DMBA. The animals received perifosin from day 0 to day 14 and were observed until day 42. The weight of the tumor mass was determined by palpation and comparison with plastic models. The initial weight is set to 100%. Administration: Perifosin 14 x 6.81 mg / kg po
Cisplatin 4 x 1 mg/kg i.p.Cisplatin 4 x 1 mg / kg i.p.
Effekt: Die Reduktion des Tumors war durch dieEffect: The reduction of the tumor was due to the
Kombinationsbehandlung deutlich stärker und länger als durch die jeweilige Einzelbehandlung.Combination treatment significantly stronger and longer than with the individual treatment.
Behandlung Tumor Tag 21 p Test vs.Treatment tumor day 21 p test vs.
Ausgangsgewicht Veränderung in [%] KontrolleStarting weight change in [%] control
[g][G]
Kontrolle 1.0 875Control 1.0 875
Perifosin (D-21266) 0.9 -25 <0.001Perifosin (D-21266) 0.9 -25 <0.001
Cisplatin 0.9 410 0.120Cisplatin 0.9 410 0.120
Perifosin (D-21266) 0.8 -75 <0.001Perifosin (D-21266) 0.8 -75 <0.001
+ Cisplatin+ Cisplatin
2. Gabe von Perifosine in Kombination mit Cyclophosphamid2. Administration of perifosine in combination with cyclophosphamide
In-vivo Versuch: DMBA induziertes Mamma-Karzinom Modell an der RatteIn-vivo experiment: DMBA-induced breast carcinoma model in the rat
Versuchstier: Sprague-Dawley Ratte, weiblichExperimental animal: Sprague-Dawley rat, female
Durchführung: Die Induktion des Mamma-Karzinoms erfolgte durch einmalige orale Gabe von DMBA. Die Tiere erhielten von Tag 0 bis Tag 14 Perifosin und wurden bis Tag 42 beobachtet. Das Gewicht der Tumormasse wurde mittels Palpation und Vergleich mit Plastikmodellen ermittelt. Das Ausgangsgewicht wird gleich 100% gesetzt.Implementation: The induction of breast cancer was carried out by a single oral administration of DMBA. The animals received perifosin from day 0 to day 14 and were observed until day 42. The weight of the tumor mass was determined by palpation and comparison with plastic models. The initial weight is set to 100%.
Gabe: Perifosin 14 x 6.81 mg/kg p.o.Administration: Perifosin 14 x 6.81 mg / kg p.o.
Cyclophosphamid 100 mg/kg, VZ 0, i.v. Effekt: Die Reduktion des Tumors war durch dieCyclophosphamide 100 mg / kg, VZ 0, iv Effect: The reduction of the tumor was due to the
Kombinationsbehandlung deutlich stärker und länger als durch die jeweilige Einzelbehandlung.Combination treatment significantly stronger and longer than with the individual treatment.
Behandlung Tumor Tag 21 p Test vs.Treatment tumor day 21 p test vs.
Ausgangsgewicht [g] Veränderung in [%] KontrolleStarting weight [g] change in [%] control
Kontrolle 1.0 875Control 1.0 875
Perifosin (D-21266) 0.9 -25 <0.001Perifosin (D-21266) 0.9 -25 <0.001
Cyclophosphamid 0.9 500 0.011Cyclophosphamide 0.9 500 0.011
Perifosin (D-21266) 0.8 -83.3 <0.001 + CyclophosphamidPerifosin (D-21266) 0.8 -83.3 <0.001 + cyclophosphamide
3. Gabe von Perifosine in Kombination mit Adriamycin3. Administration of Perifosine in combination with Adriamycin
In-vivo Versuch: DMBA induziertes Mamma-Karzinom Modell an der RatteIn-vivo experiment: DMBA-induced breast carcinoma model in the rat
Versuchstier: Sprague-Dawley Ratte, weiblichExperimental animal: Sprague-Dawley rat, female
Durchführung: Die Induktion des Mamma-Karzinoms erfolgte durch einmalige orale Gabe von DMBA. Die Tiere erhielten von Tag 0 bis Tag 14 Perifosin und wurden bis Tag 42 beobachtet. Das Gewicht der Tumormasse wurde mittels Palpation und Vergleich mit Plastikmodellen ermittelt. Das Ausgangsgewicht wird gleich 100% gesetzt.Implementation: The induction of breast cancer was carried out by a single oral administration of DMBA. The animals received perifosin from day 0 to day 14 and were observed until day 42. The weight of the tumor mass was determined by palpation and comparison with plastic models. The initial weight is set to 100%.
Gabe: Perifosin 14 x 6.81 mg/kg p.o.Administration: Perifosin 14 x 6.81 mg / kg p.o.
Adriamycin 4 x 2.15 mg/kg i.p.Adriamycin 4 x 2.15 mg / kg i.p.
Effekt: Die Reduktion des Tumors war durch dieEffect: The reduction of the tumor was due to the
Kombinationsbehandlung deutlich stärker und länger als durch die jeweilige Einzelbehandlung. Behandlung Tumor Tag 21 p Test vs.Combination treatment significantly stronger and longer than with the individual treatment. Treatment tumor day 21 p test vs.
Ausgangsgewicht Veränderung in [%] KontrolleStarting weight change in [%] control
[g][G]
Kontrolle 1.0 875Control 1.0 875
Perifosin (D-21266) 0.9 -25 O.001Perifosin (D-21266) 0.9 -25 O.001
Adriamycin 1.0 781.3 0.197Adriamycin 1.0 781.3 0.197
Perifosin (D-21266) 01.0 -70 O.001Perifosin (D-21266) 01.0 -70 O.001
+ Adriamycin + Adriamycin

Claims

Ansprüche Expectations
1. Verwendung von Alkylphosphocholinen der allgemeinen Formel I und II1. Use of alkylphosphocholines of the general formula I and II
Formel formula
Formel II Formula II
wobei unabhängig voneinander:independently of each other:
n, m, p, z eine ganze Zahl zwischen 0 und 4 bedeuten;n, m, p, z represent an integer between 0 and 4;
X O, S, NH bedeuten;X represents O, S, NH;
R H, einen geradkettigen oder verzweigten (CrC2o)-Alkyl-Rest, welcher gesättigt oder mit ein bis drei Doppel- und/oder Dreifachbindungen ungesättigt sein kann und welcher unsubstituiert oder wahlweise an dem gleichen oder an verschiedenen C-Atomen mit ein, zwei oder mehreren Halogen, Nitro, Cyano, Hydroxy, (CrC6)-Alkoxy, Amino, Mono-(CrC ) Alkylamino oder Di- (CrC4)-Alkylamino Resten substituiert sein kann, bedeutet;RH, a straight-chain or branched (CrC 2 o) -alkyl radical, which can be saturated or unsaturated with one to three double and / or triple bonds and which is unsubstituted or optionally on the same or different C atoms with one or two or more halogen, nitro, cyano, hydroxy, (CrC 6 ) alkoxy, amino, mono- (CrC) alkylamino or di- (CrC 4 ) alkylamino radicals may be substituted;
Ri, 2. R3 unabhängig von einander H, einen geradkettigen oder verzweigten (C-r C6)-Alkyl-Rest, vorzugsweise Methyl und Ethyl, einen (C3-C7)- Cycloalky-Rest und welcher unsubstituiert oder wahlweise an dem gleichen oder an verschiedenen C-Atomen mit ein, zwei oder mehreren Halogen, Nitro, Cyano, Hydroxy, (C C6)-Alkoxy, Amino, Mono-(C C4) Alkylamino oder Di- (CrC4)-Alkylamino Resten substituiert sein kann, bedeutet,Ri, 2nd R 3 independently of one another H, a straight-chain or branched (Cr C 6 ) alkyl radical, preferably methyl and ethyl, a (C 3 -C 7 ) cycloalky radical and which is unsubstituted or optionally on the same or on different C Atoms with one, two or more halogen, nitro, cyano, hydroxy, (CC 6 ) alkoxy, amino, mono- (CC 4 ) Alkylamino or di- (CrC 4 ) -alkylamino radicals can be substituted means
zur Herstellung eines Arzneimittels zur Behandlung von gutartigen und bösartigen Tumorerkrankungen vor und/oder während der Behandlung mit einem zugelassenen Antitumormedikament.for the manufacture of a medicament for the treatment of benign and malignant tumor diseases before and / or during treatment with an approved anti-tumor drug.
2. Verwendung von Alkylphosphocholinen der allgemeinen Formel I gemäß Anspruch 12. Use of alkylphosphocholines of the general formula I according to claim 1
Formel I Formula I.
wobei unabhängig voneinander:independently of each other:
n die ganze Zahl 1 oder 2 bedeutet; m die ganze Zahl 1 bedeutet;n represents the integer 1 or 2; m represents the integer 1;
X O bedeutet;X represents O;
R H, einen geradkettigen oder verzweigten (CrCι )-Alkyl-Rest, welcher gesättigt oder mit ein bis drei Doppel- und/oder Dreifachbindungen ungesättigt sein kann, bedeutet;R H, a straight-chain or branched (CrCι) alkyl radical, which may be saturated or unsaturated with one to three double and / or triple bonds, means;
R-i» R2, R3 unabhängig von einander H, einen geradkettigen oder verzweigten (C Ce)-Alkyl-Rest, vorzugsweise Methyl und Ethyl, einen (C3-C )- Cycloalky-Rest sein kann, bedeutet,Ri 'R 2, R 3 H, a straight or branched (C Ce) alkyl radical, preferably methyl and ethyl, a (C 3 -C) independently of one another - may be Cycloalky-radical,
zur Herstellung eines Arzneimittels zur Behandlung von gutartigen und bösartigen Tumorerkrankungen vor und/oder während der Behandlung mit einem zugelassenen Antitumormedikament. for the manufacture of a medicament for the treatment of benign and malignant tumor diseases before and / or during treatment with an approved anti-tumor drug.
3. Verwendung von Alkylphosphocholinen der allgemeinen Formel II gemäß Anspruch 13. Use of alkylphosphocholines of the general formula II according to claim 1
Formel II Formula II
wobei unabhängig voneinander:independently of each other:
m, p die ganze Zahl 1 bedeutet; n, z die ganze Zahl 2 bedeutet;m, p represents the integer 1; n, z represents the integer 2;
X O bedeutet;X represents O;
R H, einen geradkettigen oder verzweigten (Cι-C-ι )-Alkyl-Rest, welcher gesättigt oder mit ein bis drei Doppel- und/oder Dreifachbindungen ungesättigt sein kann, bedeutet;R H, a straight-chain or branched (-C-C-ι) alkyl radical, which may be saturated or unsaturated with one to three double and / or triple bonds;
R-i, R2, R3 unabhängig von einander H, einen geradkettigen oder verzweigten (C C6)-Alkyl-Rest, vorzugsweise Methyl und Ethyl, einen (C3-C7)-Cycloalky- Rest sein kann, bedeutet,R 1, R 2 , R 3, independently of one another, can be H, a straight-chain or branched (CC 6 ) alkyl radical, preferably methyl and ethyl, a (C 3 -C 7 ) cycloalkyl radical,
zur Herstellung eines Arzneimittels zur Behandlung von gutartigen und bösartigen Tumorerkrankungen vor und/oder während der Behandlung mit einem zugelassenen Antitumormedikament.for the manufacture of a medicament for the treatment of benign and malignant tumor diseases before and / or during treatment with an approved anti-tumor drug.
4. Verwendung von Octadecyl-(1 ,1-dimethyl-piperidinio-4-yl)-phosphat gemäß Anspruch 1 zur Herstellung eines Arzneimittels zur Behandlung von gutartigen und bösartigen Tumorerkrankungen vor und/oder während der Behandlung mit einem zugelassenen Antitumormedikament. 4. Use of octadecyl- (1, 1-dimethyl-piperidinio-4-yl) phosphate according to claim 1 for the manufacture of a medicament for the treatment of benign and malignant tumor diseases before and / or during treatment with an approved anti-tumor drug.
5. Verwendung von Alkylphosphocholinen der allgemeinen Formel I und II gemäß den Ansprüchen 1 bis 4, wobei die zugelassenen Antitumormedikamente Alkylantien, Antimetabolite, Pflanzenalkaloide, Platinverbindungen, Tumorantibiotika und Agonisten bzw. Antagonisten natürlicher Hormone sein können.5. Use of alkylphosphocholines of the general formula I and II according to claims 1 to 4, it being possible for the approved anti-tumor medications to be alkylating agents, antimetabolites, plant alkaloids, platinum compounds, tumor antibiotics and agonists or antagonists of natural hormones.
6. Verwendung nach Anspruch 5, wobei die Antitumormedikamente Cisplatin, Cyclophosphamid oder Adriamycin sein können.6. Use according to claim 5, wherein the anti-tumor drugs can be cisplatin, cyclophosphamide or adriamycin.
7. Verwendung von Alkylphosphocholinen der allgemeinen Formel I und II gemäß den Ansprüchen 1 bis 4, wobei die zugelassenen Antitumormedikamente Hemmstoffe der Signaltransduktion in Form von hoch- und niedermolekularen Inhibitoren von Rezeptor- und/oder cytosolischen Kinasen sein können.7. Use of alkylphosphocholines of the general formula I and II according to claims 1 to 4, it being possible for the approved anti-tumor medications to be signal transduction inhibitors in the form of high and low molecular weight inhibitors of receptor and / or cytosolic kinases.
8. Verwendung nach Anspruch 7, wobei die Hemmstoffe monoklonale Antikörper oder heterocyclische Verbindungen sein können.8. Use according to claim 7, wherein the inhibitors can be monoclonal antibodies or heterocyclic compounds.
9. Verwendung von Alkylphosphocholinen der allgemeinen Formel I und II nach den Ansprüchen 1 bis 8 in einer für die Behandlung wirksamen therapeutischen Dosis vor und/oder während der Behandlung mit einem zugelassenen Antitumormedikament.9. Use of alkylphosphocholines of the general formula I and II according to claims 1 to 8 in an effective therapeutic dose for the treatment before and / or during the treatment with an approved antitumor drug.
10. Verwendung von Alkylphosphocholinen der allgemeinen Formel I und II nach den Ansprüchen 1 bis 9, wobei das zugelassene Antitumormedikament eine Kombination verschiedener Zytostatika ist.10. Use of alkylphosphocholines of the general formula I and II according to claims 1 to 9, wherein the approved anti-tumor drug is a combination of different cytostatics.
11. Verwendung von Alkylphosphocholinen der Formel I und II nach den Ansprüchen 1 bis 4, zur Herstellung eines Arzneimittels zur Behandlung von gutartigen und bösartigen Tumorerkrankungen vor und/oder während der Behandlung mit einem zugelassenen Antitumormedikament, dadurch gekennzeichnet, dass das Arzneimittel neben dem Alkylphosphocholin der Formel I und II die üblichen pharmazeutischen Träger, Hilfsstoffe und/oder Verdünnungsmittel enthält. Arzneimittel, enthaltend mindestens ein Alkylphosphocholin der allgemeinen Formel I und II und gegebenenfalls Träger- und/oder Hilfsstoffe zur Verwendung in der Behandlung von gutartigen und bösartigen Tumorerkrankungen vor und/oder während der Behandlung mit einem zugelassenen Antitumormedikament. 11. Use of alkylphosphocholines of the formula I and II according to claims 1 to 4, for the manufacture of a medicament for the treatment of benign and malignant tumor diseases before and / or during treatment with an approved antitumor medicament, characterized in that the medicament in addition to the alkylphosphocholine Formula I and II contains the usual pharmaceutical carriers, auxiliaries and / or diluents. Medicaments containing at least one alkylphosphocholine of the general formula I and II and, if appropriate, carriers and / or auxiliaries for use in the treatment of benign and malignant tumor diseases before and / or during the treatment with an approved antitumor drug.
EP03766336A 2002-07-30 2003-07-29 Use of alkyl phosphocholines in combination with antitumor medicaments Expired - Lifetime EP1545553B1 (en)

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